Bardet-Biedl Syndrome (BBS) is a genetically heterogeneous, pleiotropic disorder with clinical features that include obesity and hypertension. There has been significant interest in identification of genes causing BBS and the elucidation of the pathophysiological mechanisms resulting in the clinical features of this syndrome due to the fact that components of the phenotype including obesity and hypertension are common causes of morbidity and mortality in human populations. Our group has independently identified seven of the eleven known BBS genes: BBS1, BBS2, BBS3, BBS4, BBS6, BBS9 and BBS11. Although eleven BBS genes have been identified, elucidation of BBS gene function by sequence homology to other genes with known function has proven elusive. We recently developed three different BBS mouse models by knocking out the Bbs2, Bbs4 and Bbs6 genes and demonstrated that all three models develop obesity, and that Bbs4 and Bbs6 knockout mice also have elevated arterial pressure compared to controls. The increased body mass in the knockout mice is associated with hyperleptinemia and leptin resistance, and the mice with hypertension exhibit an increase in renal sympathetic activity. Building upon this strong preliminary data, the aims of this proposal are directed at uncovering the pathophysiological mechanisms involved in obesity and high arterial blood pressure in BBS. Based on the preliminary data, we hypothesize that Central neurogenic mechanisms play a major pathophysiological role in obesity and hypertension associated with deletion of BBS genes in mice. The proposed experiments are aimed at: (1) Investigating the pathophysiological mechanisms leading to obesity in Bbs2, Bbs4 and Bbs6 knockout mice with particular focus on the role of leptin resistance and potential defects in the hypothalamic network controlling energy homeostasis. (2) Investigating the mechanisms of hypertension observed in the Bbs4 and Bbs6 knockout mice by assessing the hemodynamic, sympathetic and hormonal systems involved in blood pressure regulation; and (3) Use Bbs4 conditional knockout mice to determine whether the obesity and hypertension components of the BBS phenotype result primarily from loss of function of the gene in the central nervous system. The overall goal of the project is to uncover novel components of blood pressure and body mass regulation, and to gain insight into pathophysiological mechanisms leading to complex disorders.